A convenient preparation of glycosyl chlorides from aryl/alkyl thioglycosides

Article abstract of DOI:10.1021/ol0063050

(equation presented) Because of the vast structural diversity encountered in the field of glycobiology, versatile methods for orthogonal oligosaccharide assembly are always of interest. Reported herein is the preparation of glycosyl chloride donors obtained by reaction of the corresponding thioglycoside precursors with chlorosulfonium chloride reagent 4. The crude chlorides thus obtained can be used directly in subsequent glycosylation reactions, and examples of the generality of this approach are provided.

Full text of DOI:10.1021/ol0063050

ORGANIC
LETTERS
2000
Vol. 2, No. 17
2713-2715
A Convenient Preparation of Glycosyl
Chlorides from Aryl/Alkyl Thioglycosides
Shin Sugiyama and James M. Diakur*
Faculty of Pharmacy & Pharmaceutical Sciences, UniVersity of Alberta,
Edmonton, Alberta, Canada T6G 2N8
jdiakur@pharmacy.ualberta.ca
Received July 7, 2000
ABSTRACT
Because of the vast structural diversity encountered in the field of glycobiology, versatile methods for orthogonal oligosaccharide assembly
are always of interest. Reported herein is the preparation of glycosyl chloride donors obtained by reaction of the corresponding thioglycoside
precursors with chlorosulfonium chloride reagent 4. The crude chlorides thus obtained can be used directly in subsequent glycosylation
reactions, and examples of the generality of this approach are provided.
Thioglycosides are now well established as stable and
versatile synthons in the field of synthetic carbohydrate
chemistry.1-4 During the course of our work on oligosac-
charide assembly,5 we required a mild, versatile protocol for
the conversion of thioglycosides protected with sensitive
blocking groups into their corresponding glycosyl chlorides.
Halogen activation6,7 of thioglycosides is well-known, and
the reaction proceeds under essentially neutral conditions.
The mechanism of conversion involves the initial formation
of glycosyl halosulfonium salt 2 from thioglycoside 1, which
subsequently heterolyzes to glycosyl halide 3 (Scheme 1).
Scheme 1
(1) Garegg, P. J. AdV. Carbohydr. Chem. Biochem. 1997, 52, 179-205.
(2) Fugedi, P.; Garegg, P. J.; Lonn, H.; Noberg, T. Glycoconjugate J.
1987, 4, 97-108.
(3) Toshima, K.; Tatsuta, K. Chem. ReV. 1993, 93, 1503-1531.
(4) Norberg, T. In Modern Methods in Carbohydrate Synthesis; Khan,
S. H., O’Neill, R. A., Eds.; Harwood Academic Publishers: 1995; Chapter
4.
(5) Sugiyama, S.; Diakur, J. M. Manuscript in preparation.
(6) Bromine activation; (a) Bonner, W. J. Am. Chem. Soc. 1948, 70,
3491-3497. (b) Weygand, F.; Ziemann, H.; Bestmannn, H. J. Chem. Ber.
1958, 91, 2534-2537. (c) Weygand, F.; Ziemann, H. Justus Liebigs Ann.
Chem. 1962, 657, 179-198.
(7) Chlorine activation; (a) Wolfrom, M. L.; Groebke, W. J. Org. Chem.
1963, 28, 2986-2988. (b) Wolfrom, M. L.; Garg, H. G.; Horton, D. J.
Org. Chem. 1963, 28, 2989-2991. (c) Horton, D.; Wolfrom, M. L.; Garg,
H. G. J. Org. Chem. 1963, 28, 2992-2995.
(8) Kartha, K. P. R.; Field, R. A. Tetrahedron Lett. 1997, 38, 8233-
8236.
Recently, this approach has been extended to include reaction
with mixed halogens (I-Br, I-Cl).8 The utility of this classic
halogen activation has been demonstrated in the assembly
of higher oligosaccharides.9 However, there is some concern
that bromine can react with aromatic aryl protecting groups,10
while the handling of chlorine gas is cumbersome. Here, we
report a convenient method for the preparation of glycosyl
chlorides from their precursor thioglycosides via chlorosul-
fonium salts generated in situ.
We envisaged that a preformed sulfonium salt such as 4
could effectively participate in the transfer of chlorine to
thioglycoside 1 to generate 2. Reagent 4 is readily prepared
by treatment of an alkyl or aryl sulfoxide with oxalyl chloride
(9) (a) Koto, S.; Uchida, T.; Zen, S. Bull. Chem. Soc. 1973, 46, 2520-
2523. (b) Leontein, K.; Nilsson, M.; Norberg, T. Carbohydr. Res. 1985,
144, 231-240. (c) Norberg, T.; Ritzen, H. Glycocoonjugate J. 1986, 3,
135-142. (d) Garegg, P. J.; Haraldsson, M.; Lonn, H.; Norberg, T.
Glycoconjugate J. 1987, 4, 231-238. (e) Norberg, T.; Walding, M.;
Westman, E. J. Carbohydr. Chem. 1988, 7, 283-292. (f) Kovac, P.; Lerner,
L. Carbohydr. Res. 1988, 184, 87-112.
(11) (a) Mancuso, A. J.; Swern, D. Synthesis 1981, 165-185. (b) Omura,
K.; Swern, D. Tetrahedron 1978, 34, 1651-1660. (c) Mancuso, A. J.;
Huang, S. L.; Swern, D. J. Org. Chem. 1978, 43, 2480-2482.
(10) Kihlberg, J. O.; Leigh, D. A.; Bundle, D. R. J. Org. Chem. 1990,
55, 2860-2863.
10.1021/ol0063050 CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/03/2000

under conditions similar to those utilized for the preparation
of activated sulfoxides in the Swern oxidation.11 Initial
investigations were conducted on thioglycosides 7, 15, and
18 (Figure 1) with two chlorosulfonium salts, namely, 5 (4;
With preformed salt 5, thioglycosides 7 and 18 remained
virtually unaffected while thioglycoside 15 gave only partial
reaction, leaving substantial amounts of unreacted starting
thioglycoside. On the other hand, all three thioglycosides,
7, 15, and 18, were rapidly converted to their corresponding
glycosyl chlorides using salt 6 with no evidence of starting
materials remaining.13 The rapid reaction with salt 6 indicated
that the mechanism most likely involves the initial formation
of 2, which presumably occurs via chlorine transfer. Sub-
sequent heterolysis of 2 leads to the kinetically controlled
formation of 3. The results also showed a clear difference
in reactivity between salt 5 and 6 under the conditions
described herein. Garcia et al. reported a similar observation
in the direct glycosidation of 1-hydroxy glycosyl donors with
sulfonium salts which were generated from phenyl sulfoxide/
triflic anhydride and methyl sulfoxide/triflic anhydride.14 It
is known that the nucleophilicity of the sulfur atom of a
thioglycoside is influenced by electronic effects from both
the blocking groups of the sugar moieties (“armed-disarmed”
concept)15 and the alkyl/aryl substituents at the sulfur atom
of the aglycon (“active-latent” concept).16 Therefore, it was
assumed that effective chlorine transfer and subsequent
formation of glycosyl chlorides 3 might proceed if sulfonium
salt 4 is less electronically favored than the glycosyl
sulfonium salt 2.
Our initial findings indicated that preformed 6 is an
efficient chlorine transfer reagent; thus, the phenyl sulfoxide/
oxalyl chloride combination was selected for further study.
It was found that all of the thioglycosides shown in Figure
1 reacted readily with 6, and the starting thioglycosides were
totally consumed under these reaction conditions. The yields
of glycosyl chlorides (Table 1) obtained were typically
Table 1. Formation of Glycosyl Chlorides from Thioglycosides
glycosyl
chloride
δ (ppm) and J (for
H-1) (in CDCl3)
thioglycoside
R:â ratio
7
9
12
8
10
13/14
0:1
0:1
4.8:1
6.21 (J 10.3 Hz, â)
6.13 (J 10.0 Hz, â)
6.15 (J 3.4 Hz, R)
5.14 (J 8.8 Hz, â)
6.15 (J 3.4 Hz, R)
5.16 (J 8.3 Hz, â)
5.27 (J 8.8 Hz, â)
6.22 (J 3.9 Hz, R)
5.20 (J 8.8 Hz, â)
6.65 (J 3.9 Hz, R)
5.57 (J 8.8 Hz, â)
6.65 (J 3.9 Hz, R)
5.57 (J 8.8 Hz, â)
6.28 (J 3.4 Hz, R)
5.36 (J 8.9 Hz, â)
5.36 (J 8.9 Hz, â)
6.18 (J 9.3 Hz, â)
5.93 (J 1.5 Hz, R)
Figure 1.
15
16/17
3:2
R1 ) Me) and 6 (4; R1 ) Ph) as follows: The reaction was
performed under an argon atmosphere on 0.1 mmol (1 equiv)
of thioglycoside. To a stirred solution of oxalyl chloride (2
equiv) in dry CH2Cl2 (0.5 mL) at -78 °C was added
dropwise a solution of either methyl or phenyl sulfoxide (3
equiv) in dry CH2Cl2 (1 mL).12 After 5 min, when the
evolution of the gas ceased, a solution of thioglycoside in
dry CH2Cl2 (1 mL) was added dropwise, and the reaction
mixture was allowed to attain room temperature over a period
of 1.5 h. The mixture was diluted with CH2Cl2 (3 mL),
washed with a 1:1 (v/v) mixture of aqueous saturated
NaHCO3 and 10% Na2S2O3 (4 mL) and then H2O (4 mL),
and dried (Na2SO4), and the solvent was removed. The
18
20
19
21/22
0:1
10:1
25
26
31
27/28
27/28
33/34
9:1
4:1
6.7:1
32
35
38
34
36
39
0:1
0:1
1:0
1
residue was analyzed by H NMR spectroscopy.
>90%.17 Fortunately, 1H NMR analysis of the crude products
showed that the non-carbohydrate products in the mixture
did not interfere with the assignment of the carbohydrate
(12) Either the addition of the oxalyl chloride solution to a solution
containing the sulfoxide or the reverse addition did not lead to any notable
deleterious effects in the formation of reagents 5 or 6.
2714
Org. Lett., Vol. 2, No. 17, 2000

ring proton signals.18 The survival of the benzylidene ring
in compounds 9, 20, 25, 26, and 35 indicated that the reaction
conditions described herein are essentially neutral. Interest-
ingly, R-thioglycoside 32 gave only â-chloride 34, while
â-thioglycoside 31 gave a mixture of R- and â-chlorides,
indicating the importance of the anomeric configuration of
the starting material. Kovac and Lerner9f previously reported
differences in the outcome of glycosyl chloride formation
during chlorine activation of 6-O-acetyl-2,3,4-tri-O-benzyl-
1-thio-R- and -â-D-glucopyranosides. They likewise observed
that the R-thioglycoside gave only the â-chloride while the
â-thioglycoside led to a mixture of chlorides and additionally
demonstrated that no anomerization had occurred in either
case. This concurs with our current findings.19 Crich et al.
noted that sulfoxidation of protected R-mannothioglycosides
proceeds with high stereoselectivity20 and proposed that the
stereoselective outcome of sulfur oxidation is dependent upon
the orientation of the two lone electron pairs on the sulfur
atom. In the case of the R-thioglycoside, both steric and exo-
anomeric effects may be responsible for the high stereo-
selectivity observed. For the corresponding â-thioglycosides,
the two lone pairs are sterically less distinguishable, resulting
in mixtures of sulfoxides. It is possible that similar factors,
which are governed primarily by the anomeric configuration
of the starting thioglycoside, lead to the formation of 2 having
a preferred conformation. Such a conformation, along with
the nature of the substituent at C-2, may in turn influence
the anomeric outcome of subsequent glycosyl chloride
formation.
The utility of the crude chlorides shown in Figure 1 as
donors in typical Koenigs-Knorr type glycosidations3,21 was
demonstrated for select glycosyl acceptors to obtain glyco-
sides 11 (82%), 23 (26%), 24 (56%), 29 (44%), 30 (85%),
and 37 (82%). It was noted that the non-carbohydrate
byproducts in the crude chlorides did not interfere with the
glycosidation reactions. Isolation of chlorides 8 (92%) and
34 (87%) was achieved.
In summary, a mild method for the preparation of glycosyl
chlorides from aryl/alkyl thioglycosides has been described.
The protocol outlined herein avoids the handling of chlorine
gas, and use of the S-Ph-Cl aglycon minimizes the
unpleasant aspects of generating volatile sulfur-containing
byproducts. The reaction sequence is readily amenable to
scale-up. The procedure additionally allows for the conve-
nient generation of a wide variety of glycosyl chloride donors
in high yield and should find utility in oligosaccharide
assembly.
(13) The chloride formation was ascertained by checking AgOTf
reactivity on TLC.
(14) Garcia, B. A.; Poole, J. L.; Gin, D. Y. J. Am. Chem. Soc. 1997,
119, 7597-7598.
(15) (a) Mootoo, D. R.; Konradsson, P.; Fraser-Reid, B. J. Am. Chem.
Soc. 1989, 111, 8540-8542. (b) Mootoo, D. R.; Konradsson, P.; Udodong,
U.; Fraser-Reid, B. J. Am. Chem. Soc. 1988, 110, 5583-5584. (c) Veerman,
G. H.; van Boom, J. H. Tetrahedron Lett. 1990, 31, 275-278. (d) Veerman,
G. H.; van Leeuwen, S. H.; van Boom, J. H. Tetrahedron Lett. 1990, 31,
1131-1134. (e) Garegg, P. J.; Hallgren, C. J. Carbohydr. Chem. 1992, 11,
425-443.
Acknowledgment. This work was funded in part by a
TCP grant from the Alberta Heritage Foundation for Medical
Research.
(16) (a) Roy, R.; Anderson, F. O.; Letellier, M. Tetrahedron Lett. 1992,
33, 6053-6056. (b) Cao, S.; Hernandez-Mateo, F.; Roy, R. J. Carbohydr.
Chem. 1998, 17, 609-631.
1
Supporting Information Available: Spectral data for
compounds 7-39 and the experimental details for the
glycosylation reactions. This material is available free of
charge via the Internet at http://pubs.acs.org.
(17) In certain instances, the H NMR spectrum revealed the presence
of the hydrolysis product (<10%), presumably produced during the aqueous
workup.
(18) It was assumed that these are chlorophenyl disulfide, phenyl sulfide,
and phenyl sulfoxide on the basis of previous reports of halogen activation.
(19) The isolated â-chloride 34 was subjected to chloride formation
conditions in place of the thioglycoside. No anomerization was observed
even after the reaction mixture was left overnight at room temperature.
(20) Crich, D.; Mataka, J.; Sun, S.; Lam, K.-C.; Rheingold, A. L.; Wink,
D. J. Chem. Commun. 1998, 2763-2764.
OL0063050
(21) Igarashi, K. AdV. Carbohydr. Chem. Biochem. 1977, 34, 243-283.
Org. Lett., Vol. 2, No. 17, 2000
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